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Abstract:

This invention relates to compounds of formula I
##STR00001##
their use as positive allosteric modulators of mGlu5 receptor activity,
pharmaceutical compositions containing the same, and methods of using the
same as agents for treatment and/or prevention of neurological and
psychiatric disorders associated with glutamate dysfunction such as
schizophrenia or cognitive decline such as dementia or cognitive
impairment. A, B, Ar, R1, R2, R3, R3a have meanings
given in the description.

Claims:

1. A compound of formula I ##STR00108## in which R1 represents
phenyl, ##STR00109## Ar represents ##STR00110## the group
##STR00111## represents ##STR00112## or a physiologically acceptable
salt thereof.

3. A pharmaceutical composition comprising a therapeutically effective
amount of a compound according to claim 1 or a pharmaceutically
acceptable salt thereof in admixture with a pharmaceutically acceptable
adjuvant, diluent and/or carrier.

4. A method of treating schizophrenia, schizoaffective disorder and
substance induced psychotic disorder; cognitive disorders and dementias
including age-associated learning and memory impairments or losses, post
stroke dementia, deficits in concentration, mild cognitive impairment,
the cognitive dysfunction in Alzheimers disease or the cognitive
dysfunction of schizophrenia comprising administering to a patient a
therapeutically effective amount of a compound according to claim 1.

Description:

FIELD OF THE INVENTION

[0001] This invention relates to substituted imidazoles and their use as
positive allosteric modulators of mGlu5 receptor activity, pharmaceutical
compositions containing the same, and methods of using the same as agents
for treatment and/or prevention of neurological and psychiatric disorders
associated with glutamate dysfunction such as schizophrenia or cognitive
decline such as dementia or cognitive impairment.

BACKGROUND OF THE INVENTION

[0002] Glutamate is the primary excitatory amino acid in the mammalian
central nervous system. Neurotransmission mediated by glutamate has been
demonstrated to be critical in many physiological processes, such as
synaptic plasticity, long term potentiation involved in both learning and
memory as well as sensory perception (Riedel et al., Behav. Brain Res.
2003, 140:1-47). Furthermore, it has been demonstrated that an imbalance
of glutamate neurotransmission plays a critical role in the
pathophysiology of various neurological and psychiatric diseases.

[0003] The excitatory neurotransmission of glutamate is mediated through
at least two different classes of receptors, the ionotropic glutamate
receptors (NMDA, AMPA and kainate) and the metabotropic glutamate
receptors (mGluR). The ionotropic receptors are ligand gated ion channels
and are thought to be responsible for the regulating rapid neuronal
transmission between two neurons. The metabotropic glutamate receptors
are G-protein coupled receptors (GPCRs) which appear to mediate not only
synaptic transmission, but also to regulate the extent of
neurotransmitter release as well as post synaptic receptor activation.
Dysregulation in glutamatergic neurotransmission, for example through
altered glutamate release or post-synaptic receptor activation, has been
demonstrated in a variety of neurological ans well as psychiatric
disorders. Hypofunction of the NMDA receptor has not only been
demonstrated in Alzheimer's patients, but is increasingly accepted as the
putative cause of schizophrenia (Farber et al., Prog. Brain Res., 1998,
116: 421-437, Coyle et al., Cell. and Mol. Neurobiol. 2006, 26: 365-384).
This is supported by clinical studies showing that antagonists of the
NMDA receptor induce symptoms indistinguishable to those suffered by
schizophrenia patients (Javitt et al., Am J. Psychiatry, 1991, 148:
1301-1308). Therefore, approaches that could potentiate or normalize NMDA
receptor signaling have the potential to treat neurological and
psychiatric disorders. mGluR5 belongs to a superfamily of currently eight
identified Type III GPCRs, which are unique in that the glutamate ligand
binds to a large extracelullar amino-terminal protein domain. This
superfamily is further divided into three gropus (Group I, II and III)
based on amino acid homology as well as the intracellular signalling
cascades they regulate (Schoepp et al., Neuropharma, 1999, 38:1431-1476).
mGluR5 belongs to group I and is coupled to the phospholipase C
signalling cascade which regulates intracellular calcium mobilization.

[0004] In the CNS, mGluR5 has been demonstrated to be expressed mainly in
the cortex, hippocampus, nucleus accumbens and the caudate-putamen. These
brain regions are known to be involved in memory formation and cogntive
function as well as emotional response. mGluR5 has been shown to be
localized post-synaptically, adjacent to the post-synaptic density (Luj
an et al., Eur. J. Neurosci. 1996, 8: 1488-1500). A functional
interaction between mGluR5 and the NMDA receptor has also been
demonstrated, where activation of mGluR5 potentiates the activation state
of the NMDA receptor (Mannaioni et al, NeuroSci., 2001, 21:5925-5924,
Rosenbrock et al., Eur. J. Pharma., 2010, 639:40-46). Furthermore,
activation of mGluR5 has been demonstrated in pre-clinical in vivo models
to rescue cognitive impairment as well as psychotic disturbance induced
by NMDA receptor antagonists (Chan et al., Psychopharma. 2008,
198:141-148). Therefore, activation of mGluR5, and thereby potentiation
or normalization of the NMDA receptor signaling, is a potential mechanism
for the treatment of psychiatric and neurological disorders.

[0005] Most agonists of mGluR5 bind the orthosteric glutamate binding
site. Since the glutamate binding site between the mGluR family members
is highly conserved, it has been challenging to develop selective mGluR5
agonists which have acceptable CNS penetration and demonstrate in vivo
activity. An alternative approach to achieve selectivity between the
mGluR family members is to develop compounds which bind to an allosteric
site, which is not as highly conserved between the family members. These
allosteric binding compounds would not interfere with the natural
glutamate binding and signaling, but modulate the receptor activation
state.

[0007] WO 2003/105853 and WO 2005/056015 disclose substituted pyrazoles
that are said to be CCR1 receptor antagonists and to be useful for the
treatment of inflammation and immune disorders. Quite surprisingly,
according to the present invention, some selected imidazole derivatives
show positive modulatory activity on the mGluR5 receptor without having
an inhibitory effect on the CCR1 receptor. Such compounds are useful for
the treatment of psychotic disorders, cognitive disorders and dementias.

DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention is directed to compounds of formula I:

##STR00002##

in which

[0009] A and B independently represent CH or N;

[0010] R1
represents aryl, heteroaryl, C1-8alkyl, C3-7cycloalkyl,
--O--C1-8alkyl which latter five groups are optionally substituted
with one or more substituents selected from halogen, --CN,
C1-3alkyl, --O--C1-3alkyl;

[0011] R2, R3, R3a
independently represent --H, halogen, --CN, C1-5alkyl,
C3-5cycloalkyl, --O--C1-5alkyl which latter three groups are
optionally substituted with one or more fluorine atoms, or

[0012] R3
and R3a may together with the six-membered ring to which they are
connected form a tetrahydropyran or N-methyl imidazole ring;

[0015] In a second embodiment, in the general formula I, A, B, Ar,
R2, R3, R3a have the same meaning as defined in any of the
preceding embodiments, and

[0016] R1 represents phenyl,
C3-6cycloalkyl which latter two groups are optionally substituted
with one or more substituents selected from fluoro, C1-3alkyl.

[0017] In another embodiment, in the general formula I, A, B, R1,
R2, R3, R3a have the same meaning as defined in any of the
preceding embodiments, and

[0018] Ar represents pyridinyl, pyridazinyl,
pyrimidinyl, triazinyl, purinyl which latter five groups are optionally
substituted with one or more substituents selected from fluoro,
C1-3alkyl, --O--C1-3alkyl which latter two groups are
optionally substituted with one or more fluorine atoms.

[0019] In another embodiment, in the general formula I, Ar, R1 have
the same meaning as defined in any of the preceding embodiments, and the
group

##STR00004##

represents phenyl, benzimidazolyl, 2,3-dihydrobenzopyranyl which latter
three groups are optionally substituted with one or more substituents
selected from chloro, fluoro, C1-3alkyl, --O--C1-3alkyl, which
latter two groups are optionally substituted with one or more fluorine
atoms.

[0020] A further embodiment of the present invention comprises compounds
of formula I in which

[0021] R1 represents phenyl,
C3-6cycloalkyl which latter two groups are optionally substituted
with one or more substituents selected from fluoro, C1-3alkyl;

[0022] Ar represents pyridinyl, pyridazinyl, pyrimidinyl, triazinyl,
purinyl which latter five groups are optionally substituted with one or
more substituents selected from fluoro, C1-3alkyl, O--C1-3alkyl
which latter two groups are optionally substituted with one or more
fluorine atoms; the group

##STR00005##

[0022] represents phenyl, benzimidazolyl, 2,3-dihydrobenzopyranyl which
latter three groups are optionally substituted with one or more
substituents selected from chloro, fluoro, C1-3alkyl,
--O--C1-3alkyl, which latter two groups are optionally substituted
with one or more fluorine atoms; or a salt thereof, particularly a
physiologically acceptable salt thereof.

[0023] In another embodiment, in the general formula I, A, B, R1,
R2, R3, R3a have the same meaning as defined in any of the
preceding embodiments, and

[0024] Ar represents phenyl,

[0024] ##STR00006##

[0025] which latter eight groups are optionally
substituted with one or more substituents selected from fluoro,
C1-3alkyl, O--C1-3alkyl which latter two groups are optionally
substituted with one or more fluorine atoms.

[0026] In another embodiment, in the general formula I, Ar, R1 have
the same meaning as defined in any of the preceding embodiments, and

[0027] A represents N or CH;

[0028] B represents CH.

[0029] In another embodiment, in the general formula I, Ar, R1 have
the same meaning as defined in any of the preceding embodiments, and

[0030] A and B represent CH.

[0031] In another embodiment, in the general formula I, A, B, Ar, R2,
R3, R3a have the same meaning as defined in any of the
preceding embodiments, and

[0032] R1 represents phenyl, cyclohexyl,

##STR00007##

[0033] In another embodiment, in the general formula I, A, B, R1,
R2, R3, R3a have the same meaning as defined in any of the
preceding embodiments, and

[0034] Ar represents

##STR00008##

[0035] In another embodiment, in the general formula I, Ar, R1 have
the same meaning as defined in any of the preceding embodiments, and the
group

##STR00009##

represents

##STR00010##

[0036] A further embodiment of the present invention comprises compounds
of formula I in which

[0037] R1 represents phenyl,

[0037] ##STR00011##

[0038] Ar represents

##STR00012##

[0038] the group

##STR00013##

represents

##STR00014##

or a salt thereof, particularly a physiologically acceptable salt
thereof.

TERMS AND DEFINITIONS USED

General Definitions

[0039] Terms not specifically defined herein should be given the meanings
that would be given to them by one of skill in the art in light of the
disclosure and the context. As used in the specification, however, unless
specified to the contrary, the following terms have the meaning indicated
and the following conventions are adhered to.

[0040] In the groups, radicals, or moieties defined below, the number of
carbon atoms is often specified preceding the group, for example,
C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon
atoms. In general, for groups comprising two or more subgroups, the last
named subgroup is the radical attachment point, for example, the
substituent "aryl-C1-3-alkyl-" means an aryl group which is bound to
a C1-3-alkyl-group, the latter of which is bound to the core or to
the group to which the substituent is attached.

[0041] In case a compound of the present invention is depicted in form of
a chemical name and as a formula in case of any discrepancy the formula
shall prevail.

[0042] An asterisk is may be used in sub-formulas to indicate the bond
which is connected to the core molecule as defined.

[0043] The numeration of the atoms of a substituent starts with the atom
which is closest to the core or to the group to which the substituent is
attached.

[0044] For example, the term "3-carboxypropyl-group" represents the
following substituent:

##STR00015##

wherein the carboxy group is attached to the third carbon atom of the
propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-" or
"cyclopropylmethyl-" group represent the following groups:

##STR00016##

[0045] The asterisk may be used in sub-formulas to indicate the bond which
is connected to the core molecule as defined.

Stereochemistry/Solvates/Hydrates:

[0046] Unless specifically indicated, throughout the specification and the
appended claims, a given chemical formula or name shall encompass
tautomers and all stereo, optical and geometrical isomers (e.g.
enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates
thereof as well as mixtures in different proportions of the separate
enantiomers, mixtures of diastereomers, or mixtures of any of the
foregoing forms where such isomers and enantiomers exist, as well as
salts, including pharmaceutically acceptable salts thereof and solvates
thereof such as for instance hydrates including solvates of the free
compounds or solvates of a salt of the compound.

Salts:

[0047] The phrase "pharmaceutically acceptable" is employed herein to
refer to those compounds, materials, compositions, and/or dosage forms
which are, within the scope of sound medical judgment, suitable for use
in contact with the tissues of human beings and animals without excessive
toxicity, irritation, allergic response, or other problem or
complication, and commensurate with a reasonable benefit/risk ratio.

[0049] The pharmaceutically acceptable salts of the present invention can
be synthesized from the parent compound which contains a basic or acidic
moiety by conventional chemical methods. Generally, such salts can be
prepared by reacting the free acid or base forms of these compounds with
a sufficient amount of the appropriate base or acid in water or in an
organic diluent like ether, ethyl acetate, ethanol, isopropanol, or
acetonitrile, or a mixture thereof.

[0050] Salts of other acids than those mentioned above which for example
are useful for purifying or isolating the compounds of the present
invention (e.g. trifluoro acetate salts,) also comprise a part of the
invention.

[0052] The term "C1-n-alkyl", wherein n is an integer from 2 to n,
either alone or in combination with another radical denotes an acyclic,
saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
For example the term C1-5-alkyl embraces the radicals H3C--,
H3C--CH2--, H3C--CH2--CH2--,
H3C--CH(CH3)--, H3C--CH2--CH2--CH2--,
H3C--CH2--CH(CH3)--, H3C--CH(CH3)--CH2--,
H3C--C(CH3)2--,
H3C--CH2--CH2--CH2--CH2--,
H3C--CH2--CH2--CH(CH3)--,
H3C--CH2--CH(CH3)--CH2--,
H3C--CH(CH3)--CH2--CH2--,
H3C--CH2--C(CH3)2--,
H3C--C(CH3)2--CH2--,
H3C--CH(CH3)--CH(CH3)-- and
H3C--CH2--CH(CH2CH3)--.

Cycloalkyl:

[0053] The term "C3-n-cycloalkyl", wherein n is an integer from 4 to
n, either alone or in combination with another radical denotes a cyclic,
saturated, unbranched hydrocarbon radical with 3 to n C atoms. For
example the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl.

Aryl:

[0054] The term "aryl" as used herein, either alone or in combination with
another radical, denotes a carbocyclic aromatic monocyclic group
containing 6 carbon atoms which may be further fused to a second 5- or
6-membered carbocyclic group which may be aromatic, saturated or
unsaturated. Aryl includes, but is not limited to, phenyl, indanyl,
indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and
dihydronaphthyl.

Heteroaryl:

[0055] The term "heteroaryl" means a mono- or polycyclic-ring systems
containing one or more heteroatoms selected from N, O or S(O)r,
wherein r=0, 1 or 2, consisting of 5 to 14 ring atoms wherein at least
one of the heteroatoms is part of aromatic ring. The term "heteroaryl" is
intended to include all the possible isomeric forms.

[0056] Thus, the term "heteroaryl" includes the following exemplary
structures which are not depicted as radicals as each form may be
attached through a covalent bond to any atom so long as appropriate
valences are maintained:

##STR00017## ##STR00018##

[0057] Many of the terms given above may be used repeatedly in the
definition of a formula or group and in each case have one of the
meanings given above, independently of one another.

GENERAL METHOD OF PREPARATION

[0058] Compounds of the present invention can be prepared in accordance
with techniques that are well known to those skilled in the art.

[0059] Compounds of the present invention can be synthesized according to
scheme 1.

##STR00019##

[0060] 2-bromo-phenyl-ethanone derivates were reacted with several
benzamidine derivates to give the desired 1H-imidazoles. 1H-imidazoles
were coupled with methyl bromoacetate to the 1H-imidazoles-2yl esters,
which were hydrolyzed with aqueous lithium hydroxide solution or aqueous
sodium hydroxide solution. Finally, the 1H-imidazol-2-yl-acetic acid
lithium salts were directly coupled with aryl substituted piperazines to
the desired products.

[0061] A subseries of compounds can be synthesized according to scheme 2:

##STR00020##

[0062] Methyl bromo acetate reacted with 2,4,5-tribromoimidazole to
(2,4,5-tribromo-imidazol-1-yl)-acetic acid methyl ester. The ester was
hydrolyzed with aqueous sodiumhydroxide solution to the corresponding
acid. The acid was coupled with aryl piperazines under basic condition to
the desired amids, followed by a Suzuki-reaction with different boronic
acids. The resulting imidazol-1-yl-piperazin-ethanones were dehalogenated
with butyllithium solution and subsequently coupled with different
boronic acids to provide the desired products.

[0063] As an additional alternative, the compounds of this invention can
be synthesized according to scheme 3:

##STR00021##

[0064] The imidazole-derivatives were available commercially available or
synthesized according to scheme 1. Coupling with
bromo-arylpiperazinyl-ethanone derivates provided the desired products.

Biological Assay

[0065] The positive modulation of mGluR5 is measured in a HEK 293 cell
line expressing human recombinant mGluR5 and is detected with calcium
based FLIPR assay. The cells are cultured with DMEM supplemented with 10%
FCS, 2 μg/mL tetracycline, 100 μg/mL hygromycin and 500 μg/mL
gneticin. The cell culture media is exchanged for tetracycline-free cell
culture media 3-7 days before the assay. One day before the assay the
cell culture medium is exchanged to DMEM without glutamine and phenol red
and supplemented with 10% FCS, 100 μg/mL hygromycin and 500 μg/mL
geneticin. On the assay day, the medium of the subconfluent cultures is
removed and the cells are detached by addition of 2.5 ml EDTA (0.02%) per
175 cm2 culture flask for 1 minute. The cells are resuspend in Ringer
solution (140 mM NaCl, 5 mM KCl, 2.5 mM CaCl2, 1.5 mM MgCl2, 5 mM
Glucose, 10 mM Hepes; adjusted to pH 7.4 with NaOH), pooled and Ringer
solution added to adjust the volume to 50 mL. The cell suspension is
centrifuged for 5 mM at 1500 U/min (425 g). The supernatant is removed
and the cells washed a second time with 50 ml fresh Ringer solution and
centrifuged again as before. The supernatant is again removed and the
pellet resuspended in Ringer solution to 1,000,000 cells/ml (1×10 6
cells/mL). The cells are plated onto BD BioCoat Poly-D-Lysine 384 well
plates (20.000 cells/well; 20 μl/well). The lid covered plates are
then incubated until use at 37° C./10% CO2. For dye loading,
20 μl of Calcium-4 assay kit solution (prepared according to the
manufacturer's description in Ringer solution) are added to the cells and
the plates are incubated for 80 mM 37° C. and then 10 mM at room
temperature.

[0070] Test compounds are dissolved and diluted in DMSO to 100-fold the
desired concentrations. In a second step, the compounds are diluted in
Ringer solution such that the compounds are 4-fold more concentrated than
the desired final assay concentration. The final DMSO concentration was
1%.

[0071] 20 μl of each compound solution are then transferred to the
assay plate and the Ca2+ kinetic is measured to determine any intrinsic
compound activity. After 5 mM incubation in the FLIPR device, the second
stimulation with 20 μl of glutamate in Ringer solution (glutamate
concentration adjusted to approximately 5% basal stimulation of the
maximal possible glutamate effect) is added and the kinetic Ca2+ response
of the wells was measured for the modulation effect.

Analysis:

[0072] The peak height of the Ca release related fluorescence signal
(9-66) is used for the EC50. The EC50 of the modulation is calculated
over a nonlinear regression with GraphPad Prism (Table 1).

[0073] The present invention is directed to compounds of general formula I
which are useful in the treatment of a disease and/or condition wherein
the activity of an mGluR5 positive modulator is of therapeutic benefit,
including but not limited to the treatment of psychotic disorders,
cognitive disorders and dementias.

[0074] The compounds of general formula I are useful for the treatment of
psychotic disorders including schizophrenia, schizoaffective disorder and
substance induced psychotic disorder; cognitive disorders and dementias
including age-associated learning and memory impairments or losses, post
stroke dementia, deficits in concentration, mild cognitive impairment,
the cognitive dysfunction in Alzheimers disease, and the cognitive
dysfunction of schizophrenia. Therefore, the present invention also
relates to a compound of general formula I as a medicament.

[0075] A further aspect of the present invention relates to the use of a
compound of general formula I for the treatment of a disease and/or
condition wherein the activity of mGluR5 positive modulator is of
therapeutic benefit.

[0076] Furthermore, the present invention relates to the use of a compound
of general formula I for the treatment of psychotic disorders, cognitive
disorders and dementias.

[0077] Furthermore, the present invention relates to the use of a compound
of general formula I for the treatment of psychotic disorders including
schizophrenia, schizoaffective disorder and substance induced psychotic
disorder; cognitive disorders and dementias including age-associated
learning and memory impairments or losses, post stroke dementia, deficits
in concentration, mild cognitive impairment, the cognitive dysfunction in
Alzheimers disease, and the cognitive dysfunction of schizophrenia.

[0078] In a further aspect of the present invention the present invention
relates to methods for the treatment or prevention of above mentioned
diseases and conditions, which method comprises the administration of an
effective amount of a compound of general formula Ito a human being.

Dosage

[0079] The dose range of the compounds of general formula I applicable per
day is usually from 0.1 to 5000 mg, preferably from 0.1 to 1000 mg, more
preferably from 5 to 500 mg, most preferably, 10 or 100 mg. Each dosage
unit may conveniently contain from 0.1 to 500 mg, preferably 10 to 100
mg.

[0080] The actual pharmaceutically effective amount or therapeutic dosage
will of course depend on factors known by those skilled in the art such
as age and weight of the patient, route of administration and severity of
disease. In any case the combination will be administered at dosages and
in a manner which allows a pharmaceutically effective amount to be
delivered based upon patient's unique condition.

Pharmaceutical Compositions

[0081] Suitable preparations for administering the compounds of formula
will be apparent to those with ordinary skill in the art and include for
example tablets, pills, capsules, suppositories, lozenges, troches,
solutions, syrups, elixirs, sachets, injectables, inhalatives and powders
etc. The content of the pharmaceutically active compound(s) should be in
the range from 1 to 99 wt.-%, preferably 10 to 90 wt.-%, more preferably
20 to 70 wt.-%, of the composition as a whole. Suitable tablets may be
obtained, for example, by mixing one or more compounds according to
formula I with known excipients, for example inert diluents, carriers,
disintegrants, adjuvants, surfactants, binders and/or lubricants. The
tablets may also consist of several layers. A further aspect of the
invention is a pharmaceutical formulation including a compound of formula
I in admixture with a pharmaceutically acceptable adjuvant, diluent or
carrier.

Combination Therapy

[0082] In another aspect the present invention relates to a combination
therapy in which an active compound according to the present invention is
administered together with another active compound. Accordingly, the
invention also refers to pharmaceutical formulations that provide such a
combination of active ingredients, whereby one of which is an active
compound of the present invention. Such combinations may be fixed dose
combinations (the active ingredients that are to be combined are subject
of the same pharmaceutical formulation) or free dose combinations (active
ingredients are in separate pharmaceutical formulations). Consequently, a
further aspect of the present invention refers to a combination of each
of the active compounds of the present invention, preferably at least one
active compound according to the present invention, with another active
compound for example selected from the group of antipsychotics such as
haloperidol, clozapine, risperidone, quetiapine, aripripazole, and
olanzapine; antidepressants such as selective serotonin re-uptake
inhibitors and dual serotonin/noradrenaline re-uptake inhibitors; mood
stabilizers such as lithium valproate and lamotrigine; beta-secretase
inhibitors; gamma-secretase inhibitors; gamma-secretase modulators;
amyloid aggregation inhibitors such as e.g. scyllo-inositol; directly or
indirectly acting neuroprotective and/or disease-modifying substances;
anti-oxidants, such as e.g. vitamin E, ginko biloba or ginkolide;
anti-inflammatory substances, such as e.g. Cox inhibitors, NSAIDs
additionally or exclusively having AB (Abeta) lowering properties;
HMG-CoA reductase inhibitors, such as statins; acetylcholine esterase
inhibitors, such as donepezil, rivastigmine, tacrine, galantamine; NMDA
receptor antagonists such as e.g. memantine; AMPA receptor agonists; AMPA
receptor positive modulators, AMPkines, glycine transporter 1 inhibitors;
monoamine receptor reuptake inhibitors; substances modulating the
concentration or release of neurotransmitters; substances inducing the
secretion of growth hormone such as ibutamoren mesylate and capromorelin;
CB-1 receptor antagonists or inverse agonists; antibiotics such as
minocyclin or rifampicin; PDE1, PDE2, PDE4, PDE5, PDE9 or PDE10
inhibitors, GABAA receptor inverse agonists; GABAA alpha5 receptor
inverse agonists; GABAA receptor antagonists; nicotinic receptor agonists
or partial agonists or positive modulators; alpha4beta2 nicotinic
receptor agonists or partial agonists or positive modulators; alpha7
nicotinic receptor agonists or partial agonists; histamine receptor H3
antagonists; 5-HT4 receptor agonists or partial agonists; 5-HT6 receptor
antagonists; alpha2-adrenoreceptor antagonists, calcium antagonists;
muscarinic receptor M1 agonists or partial agonists or positive
modulators; muscarinic receptor M2 antagonists; muscarinic receptor M4
antagonists; muscarinic receptor M4 positive allosteric modulators;
metabotropic glutamate receptor 5 positive allosteric modulators;
metabotropic glutamate receptor 2 antagonists; metabotropic glutamate
receptor 2/3 agonists; metabotropic glutamate receptor 2 positive
allosteric modulators and other substances that modulate receptors or
enzymes in a manner such that the efficacy and/or safety of the active
compounds according to the invention is increased and/or unwanted side
effects are reduced.

[0083] The active compounds according to the invention may also be used in
combination with immunotherapies such as e.g. active immunisation with
Abeta or parts thereof or passive immunisation with humanised anti-Abeta
antibodies, nanobodies or antibody fragments for the treatment of the
above mentioned diseases and conditions.

[0085] The active compounds according to the invention also may be
combined with antidepressants like amitriptyline imipramine
hydrochloride, imipramine maleate, lofepramine, desipramine, doxepin,
trimipramine.

[0087] The combinations according to the present invention may be provided
simultaneously in one and the same dosage form, i.e. in form of a
combination preparation, for example the two components may be
incorporated in one tablet, e.g. in different layers of said tablet. The
combination may be also provided separately, in form of a free
combination, i.e. the active compounds of the present invention are
provided in one dosage form and one or more of the above mentioned
combination partners is provided in another dosage form. These two dosage
forms may be equal dosage forms, for example a co-administration of two
tablets, one containing a therapeutically effective amount of the active
compound of the present invention and one containing a therapeutically
effective amount of the above mentioned combination partner. It is also
possible to combine different administration forms, if desired. Any type
of suitable administration forms may be provided.

[0088] The active compound according to the invention, or a
physiologically acceptable salt thereof, in combination with another
active substance may be used simultaneously or at staggered times, but
particularly close together in time. If administered simultaneously, the
two active substances are given to the patient together; if administered
at staggered times the two active substances are given to the patient
successively within a period of less than or equal to 12, particularly
less than or equal to 6 hours.

[0089] The dosage or administration forms are not limited, in the frame of
the present invention any suitable dosage form may be used. Exemplarily
the dosage forms may be selected from solid preparations such as patches,
tablets, capsules, pills, pellets, dragees, powders, troches,
suppositories, liquid preparations such as solutions, suspensions,
emulsions, drops, syrups, elixirs, or gaseous preparations such as
aerosols, sprays and the like.

[0090] The dosage forms are advantageously formulated in dosage units,
each dosage unit being adapted to supply a single dose of each active
component being present. Depending from the administration route and
dosage form the ingredients are selected accordingly.

[0091] The dosage for the above-mentioned combination partners may be
expediently 1/5 of the normally recommended lowest dose up to 1/1 of the
normally recommended dose.

[0092] The dosage forms are administered to the patient for example 1, 2,
3, or 4 times daily depending on the nature of the formulation. In case
of retarding or extended release formulations or other pharmaceutical
formulations, the same may be applied differently (e.g. once weekly or
monthly etc.). It is preferred that the active compounds of the invention
be administered either three or fewer times, more preferably once or
twice daily.

EXPERIMENTAL SECTION

Preparation of Examples for Compounds of the General Formula I

[0093] Unless otherwise stated, one or more tautomeric forms of compounds
of the examples described hereinafter may be prepared in situ and/or
isolated. All tautomeric forms of compounds of the examples described
hereinafter should be considered to be disclosed.

[0094] The invention is illustrated by way of the following examples, in
which the following abbreviations may be employed:

[0112] All compounds specified in the examples below gave the correct mass
spectra matching the theoretical isotope pattern. For practical reasons,
only one of the major isotope peaks is given as representative data for
the mass spectrum.

[0179] 6.95 mL bromacetylbromide was dropped to 11.68 mL
1-pyridin-2-yl-piperazine and 11.23 mL triethylamine in 300 mL DCM at
0° C. The reaction was stirred 2 h at 0° C. The reaction
mixture was added to water and extracted with DCM. The organic layer was
dried with magesium sulfate and evaporated The residue was purified by
chromatography on silica gel (DCM/MeOH 0-20%; 0.1% ammonia) to yield 23.6
g of the desired compound.

[0183] 1.5 g piperazine-1-carboxylic acid tert-butyl ester was added to
1.2 g 2-chlor-5-methoxy-pyrimidine and 2.2 mL triethylamine in 30 mL DMF.
The reaction was stirred 6 days at 60° C. The solvent was removed
and the residue was dissolved in dichlormethane and extracted with water.
The organic layer was washed with a saturated sodiumchloride-solution and
evaporated. The residue was purified by HPLC to give 957 mg desired
product.

[0189] 0.67 mL bromine was added to 2 g
1-(4-fluoro-3-methyl-phenyl)-ethanone in 10 mL conc. acetic acid. The
reaction was stirred for 3 h at RT and added to ice water. The
precipitate was filtered, washed with water and dried to give 2.7 g
desired product.

[0190] Rt: 1.10 min (method B), (M+H).sup.+: 231

[0191] By using the same synthesis strategy as for
2-bromo-1-(4-fluoro-3-methyl-phenyl)-ethanone the following compound was
obtained:

[0193] 1.76 g potassium hydrogen carbonate in 15 mL water was added to
1.41 g benzamidine in 50 mL THF. The mixture was warmed up to 60°
C. and 2.7 g 2-bromo-1-(4-fluoro-3-methyl-phenyl)-ethanone was added. The
reaction was refluxed 5 h. The solvent was removed, water was added to
the residue and the aqueous mixture extracted with ethyl acetate. The
organic layer was dried and evaporated. The residue was purified by HPLC
to give 2.3 g desired product.

[0194] Rt: 0.96 min (method B), (M+H).sup.+: 253

[0195] By using the same synthesis strategy as for
4-(4-fluoro-3-methyl-phenyl)-2-phenyl-1H-imidazole the following
compounds were obtained:

[0200] A mixture of 220 mg lithiumhydroxide and 5 mL water was added to 1
g (4-(4-fluoro-3-methyl-phenyl)-2-phenyl-imidazol-1-yl)-acetic acid
methyl ester in 15 mL THF. The reaction mixture was stirred overnight at
RT and evaporated. Water was added to the residue and the mixture was
acidified with 1 mol/L aqueous HCL solution. The precipitate was filtered
and dried to give 540 mg desired product. Rt: 0.86 min (method B),
(M+H).sup.+: 311

[0201] By using the same synthesis strategy as for
(4-(4-fluoro-3-methyl-phenyl)-2-phenyl-imidazol-1-yl)-acetic acid the
following compounds were obtained:

[0205] 0.38 mL methyl bromoacetate was added to 940 mg
2-cyclohexyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazole and 1.52 g
potassium carbonate in 10 mL DMF. The reaction was stirred over night at
RT and evaporated. Methanol and 1 mol/L sodiumhydroxide solution was
added and the mixture was stirred 2 h at RT. The solvent was removed. The
residue was dissolved in water and acidified with 1 mol/L HCL solution.
The precipitate was filtered and dried to give 700 mg desired product.
Rt: 0.92 min (method B), (M+H).sup.+: 317

[0207] 5.1 mL methyl bromo acetate was added to 15 g
2,4,5-tribromoimidazole and 20.4 g potassium carbonate in 100 mL DMF. The
reaction was stirred 3 h at RT. The mixture was added to water. The
precipitate was filtered, washed with water and dried to give 18.1 g
desired product.

[0208] Rt: 0.93 min (method B), ESI.sup.+: 375

6.02.06 (2,4,5-tribromo-imidazol-1-yl)-acetic acid

##STR00047##

[0209] 6.02.06.01 (2,4,5-tribromo-imidazol-1-yl)-acetic acid

[0210] 18 mL 4 mol/L aqueous sodiumhydroxide solution was added to 18.1 g
(2,4,5-tribromo-imidazol-1-yl)-acetic acid methyl ester in 200 mL MeOH.
The reaction was stirred 1 h at RT and evaporated. Water was added to the
residue and the resulting mixture acidified with 1 mol/L aqueous HCL
solution. The precipitate was filtered and dried to give 17.2 g desired
product.

[0217] 9.4 mL 2.5 mol/L butyllithium solution in THF was added dropwise to
11.8 g 2-(4,5-dibromo-2-phenyl-imidazol-1-yl)-1-(4-pyrimidin-2-yl-piperaz-
in-1-yl)-ethanone in 150 mL THF at -78° C. under argon. The
reaction mixture was stirred 2 h at -78° C. followed by careful
and dropwise addition of water to the mixture. The resulting mixture was
stirred 30 min at -78° C. and then again water was added at
0° C. The mixture was extracted with ethyl acetate. The organic
layer was dried and evaporated. The residue was purified chromatoraphie
on silica (petrolether 1/ethylacetate 1). Diisopropylether was added to
the residue and the precipitate was filtered and dried to give 1.7 g
desired product. Rt: 0.94 (method B), ESI.sup.+: 427